Photoluminescence spectral broadening, chirality transfer and amplification of chiral perovskite materials (R-X-p-mBZA)2PbBr4 (X = H, F, Cl, Br) regulated by van der Waals and halogen atoms interactions.

In this work, we introduced halogen-substituted chiral molecules as A-site cations to synthesize a series of novel organic-inorganic hybrid two-dimensional (2D) chiral perovskite materials (R-X-p-mBZA)2PbBr4 (X = H, F, Cl, Br; p: para-position; mBZA = α-methylbenzylamine) for the first time. This halogen-substituted cation strategy collectively solved problems of narrow emission, weak chirality and low photoluminescence quantum yield (PLQY) for the emerged chiral perovskites. Photoluminescence (PL) spectra are significantly broadened due to the additional emission from self-trapped excitons (STEs) besides free excitons (FEs) states modulated by introducing significant disorder to the Pb-Br-Pb angle. The chirality of A-site chiral molecules is transferred and amplified to entire perovskite materials by fixing the chiral molecules at A-site via the interaction of halogen atoms. Furthermore, their PLQYs are improved with the reduction of energy gap and inhibition of the non-radiative transition from STEs to ground state. The halogen-substituted A-site cation strategy can be performed to develop organic-inorganic hybrid chiral perovskites with various optoelectronic applications.

3D-Printed Porous Tantalum Scaffold Improves Muscle Attachment via Integrin-ß1-Activated AKT/MAPK Signaling Pathway.

3D-printed porous titanium (Ti) alloy scaffolds have been reported for facilitating muscle attachment in our previous study. However, the anti-avulsion ability needs to be improved. In this study, we used 3D-printed porous tantalum (Ta) scaffolds to improve muscle attachment. The differences in chemical and physical characteristics and muscle adhesion between the two scaffolds were tested and compared in the gene and protein level both in vitro and in vivo. The possible molecular mechanism was analyzed and further proved. The results showed that compared with the porous Ti alloy, porous Ta had better cell proliferation, differentiation, migration, and adhesion via the integrin-ß1 (Itgb1)-activated AKT/MAPK signaling pathway in L6 rat myoblasts. When artificially down-regulated the expression of Itgb1, cell adhesion and myogenesis differentiation were affected and the phosphorylation of the AKT/MAPK signaling pathway was suppressed. In rat intramuscular implantation, porous Ta had a significantly higher muscle ingrowth rate (85.63% ± 4.97 vs 65.98% ± 4.52, p < 0.01) and larger avulsion force (0.972 vs 0.823 N/mm2, p < 0.05) than the porous Ti alloy. These findings demonstrate that the 3D-printed porous Ta scaffold is beneficial for further clinical application of muscle attachment.

Intra-articular treatment of temporomandibular joint osteoarthritis by injecting actively-loaded meloxicam liposomes with dual-functions of anti-inflammation and lubrication.

Temporomandibular joint (TMJ) osteoarthritis is a common osteochondral degenerative disease which can severely affect patient's mouth opening and mastication. Meloxicam (MLX), one of the most widely used non-steroidal anti-inflammatory drugs, is the main clinical therapy for the treatment of TMJ osteoarthritis. However, the clinical effect is greatly compromised because of its poor water solubility and high lipophilicity. In the present study, we developed an actively-loaded liposomal formulation, namely MLX-Ca(AC)2Lipo, using meglumine to enhance aqueous solubility and divalent metal (Ca2+) solution to improve encapsulation efficiency. By the formation of the nano-bowl shaped MLX-Ca precipitates inside the liposomes, MLX-Ca(AC)2Lipo successfully achieved an optimal encapsulation efficiency as high as 98.4% compared with previous passive loading method (60.6%). Additionally, MLX-Ca(AC)2Lipo maintained stable, and the slow drug release not only prolonged the duration of drug efficacy but also improved bioavailability. It was shown in the in vitro and in vivo tests that MLX-Ca(AC)2Lipo downregulated the synthesis of the inflammatory factors (such as prostaglandin-E2) and as a consequence reduced chondrocytes apoptosis and extracellular matrix degeneration. Furthermore, the intra-articular injection of MLX-Ca(AC)2Lipo enhanced bioinspired lubrication of TMJ, protecting the cartilage from progressive wear. In summary, MLX-Ca(AC)2Lipo with dual-functions of anti-inflammation and lubrication is a promising nanomedicine for the treatment of TMJ osteoarthritis by intra-articular injection.

Oncolytic virus M1 functions as a bifunctional checkpoint inhibitor to enhance the antitumor activity of DC vaccine.

Although promising, dendritic cell (DC) vaccines still provide limited clinical benefits, mainly due to the immunosuppressive tumor microenvironment (TME) and the lack of tumor-associated antigens (TAAs). Oncolytic virus therapy is an ideal strategy to overcome immunosuppression and expose TAAs; therefore, they may work synergistically with DC vaccines. In this study, we demonstrate that oncolytic virus M1 (OVM) can enhance the antitumor effects of DC vaccines across diverse syngeneic mouse tumor models by increasing the infiltration of CD8+ effector T cells in the TME. Mechanically, we show that tumor cells counteract DC vaccines through the SIRPα-CD47 immune checkpoint, while OVM can downregulate SIRPα in DCs and CD47 in tumor cells. Since OVM upregulates PD-L1 in DCs, combining PD-L1 blockade with DC vaccines and OVM further enhances antitumor activity. Overall, OVM strengthens the antitumor efficacy of DC vaccines by targeting the SIRPα-CD47 axis, which exerts dominant immunosuppressive effects on DC vaccines.

Differential regulation of H3K9/H3K14 acetylation by small molecules drives neuron-fate-induction of glioma cell.

Differentiation therapy using small molecules is a promising strategy for improving the prognosis of glioblastoma (GBM). Histone acetylation plays an important role in cell fate determination. Nevertheless, whether histone acetylation in specific sites determines GBM cells fate remains to be explored. Through screening from a 349 small molecule-library, we identified that histone deacetylase inhibitor (HDACi) MS-275 synergized with 8-CPT-cAMP was able to transdifferentiate U87MG GBM cells into neuron-like cells, which were characterized by cell cycle arrest, rich neuron biomarkers, and typical neuron electrophysiology. Intriguingly, acetylation tags of histone 3 at lysine 9 (H3K9ac) were decreased in the promoter of multiple oncogenes and cell cycle genes, while ones of H3K9ac and histone 3 at lysine 14 (H3K14ac) were increased in the promoter of neuron-specific genes. We then compiled a list of genes controlled by H3K9ac and H3K14ac, and proved that it is a good predictive power for pathologic grading and survival prediction. Moreover, cAMP agonist combined with HDACi also induced glioma stem cells (GSCs) to differentiate into neuron-like cells through the regulation of H3K9ac/K14ac, indicating that combined induction has the potential for recurrence-preventive application. Furthermore, the combination of cAMP activator plus HDACi significantly repressed the tumor growth in a subcutaneous GSC-derived tumor model, and temozolomide cooperated with the differentiation-inducing combination to prolong the survival in an orthotopic GSC-derived tumor model. These findings highlight epigenetic reprogramming through H3K9ac and H3K14ac as a novel approach for driving neuron-fate-induction of GBM cells.

Disruption of ß-catenin-mediated negative feedback reinforces cAMP-induced neuronal differentiation in glioma stem cells.

Accumulating evidence supports the existence of glioma stem cells (GSCs) and their critical role in the resistance to conventional treatments for glioblastoma multiforme (GBM). Differentiation therapy represents a promising alternative strategy against GBM by forcing GSCs to exit the cell cycle and reach terminal differentiation. In this study, we demonstrated that cAMP triggered neuronal differentiation and compromised the self-renewal capacity in GSCs. In addition, cAMP induced negative feedback to antagonize the differentiation process by activating ß-catenin pathway. Suppression of ß-catenin signaling synergized with cAMP activators to eliminate GSCs in vitro and extended the survival of animals in vivo. The cAMP/PKA pathway stabilized ß-catenin through direct phosphorylation of the molecule and inhibition of GSK-3ß. The activated ß-catenin translocated into the nucleus and promoted the transcription of APELA and CARD16, which were found to be responsible for the repression of cAMP-induced differentiation in GSCs. Overall, our findings identified a negative feedback mechanism for cAMP-induced differentiation in GSCs and provided potential targets for the reinforcement of differentiation therapy for GBM.

A Novel Design of Temporomandibular Joint Prosthesis for Lateral Pterygoid Muscle Attachment: A Preliminary Study.

Introduction: In temporomandibular joint (TMJ) replacement operation, due to the condylectomy, the lateral pterygoid muscle (LPM) lost attachment and had impact on the mandible kinematic function. This study aimed to design a novel TMJ replacement prosthesis for LPM attachment and to verify its feasibility by preliminary in vitro and in vivo experiments. Materials and Methods: An artificial TMJ prosthesis designed with a porous structure on the condylar neck region for LPM attachment was fabricated by a 3D printed titanium (Ti) alloy. A rat myoblast cell line (L6) was tested for adhesion and biocompatibility with porous titanium scaffolds in vitro by cell counting Kit-8 (CCK-8), scanning electron microscope (SEM), flow cytometry (FCM), real-time quantitative polymerase chain reaction (RT-qPCR), immunocytofluorescense, western blotting, etc. The porous titanium scaffolds were further embedded in the rat intervertebral muscle to analyze muscle growth and biomechanical strength in vivo. The novel artificial TMJ prosthesis was implanted to reconstruct the goat's condyle and LPM reattachment was analyzed by hard tissue section and avulsion force test. Results: L6 muscle cells showed good proliferation potential on the porous Ti scaffold under SEM scanning and FCM test. In RT-qPCR, immunocytofluorescense and western blotting tests, the L6 cell lines had good myogenic capacity when cultured on the scaffold with high expression of factors such as Myod1 and myoglobin, etc. In the in vivo experiment, muscles penetrated into the porous scaffold in both rats and goats. In rat's intervertebral muscle implantation, the avulsion force was 0.716 N/mm2 in 4 weeks after operation and was significantly increased to 0.801 N/mm2 at 8 weeks (p < 0.05). In goat condylar reconstruction with the porous scaffold prosthesis, muscles attached to the prosthesis with the avulsion force of 0.436 N/mm2 at 8 weeks, but was smaller than the biological muscle-bone attachment force. Conclusion: The novel designed TMJ prosthesis can help LPM attach to its porous titanium scaffold structure area for future function.